6-83853449-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001009994.3(RIPPLY2):c.33G>C(p.Glu11Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,543,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E11E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

RIPPLY2
NM_001009994.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.117

Publications

0 publications found

Variant links:

Genes affected

RIPPLY2 (HGNC:21390): (ripply transcriptional repressor 2) This gene encodes a nuclear protein that belongs to a novel family of proteins required for vertebrate somitogenesis. Members of this family have a tetrapeptide WRPW motif that is required for interaction with the transcriptional repressor Groucho and a carboxy-terminal Ripply homology domain/Bowline-DSCR-Ledgerline conserved region required for transcriptional repression. Null mutant mice die soon after birth and display defects in axial skeleton segmentation due to defective somitogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

RIPPLY2 Gene-Disease associations (from GenCC):

spondylocostal dysostosis 6, autosomal recessive
Inheritance: AR, Unknown Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
autosomal recessive spondylocostal dysostosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

RIPPLY2 links:

ENSG00000287705 (HGNC:):

ENSG00000287705 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08111042).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009994.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RIPPLY2	NM_001009994.3	MANE Select	c.33G>C	p.Glu11Asp	missense	Exon 1 of 4	NP_001009994.1	Q5TAB7-1
RIPPLY2	NM_001400900.1		c.33G>C	p.Glu11Asp	missense	Exon 1 of 3	NP_001387829.1
RIPPLY2-CYB5R4	NR_174604.1		n.90G>C		non_coding_transcript_exon	Exon 1 of 18

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RIPPLY2	ENST00000369689.6	TSL:1 MANE Select	c.33G>C	p.Glu11Asp	missense	Exon 1 of 4	ENSP00000358703.1	Q5TAB7-1
ENSG00000287705	ENST00000656981.1		n.719C>G		non_coding_transcript_exon	Exon 1 of 1
RIPPLY2	ENST00000369687.2	TSL:2	c.-325G>C		upstream_gene	N/A	ENSP00000358701.1	Q5TAB7-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000730

AC:

AN:

136996

AF XY:

0.0000134

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000200

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000129

AC:

AN:

1391516

Hom.:

Cov.:

AF XY:

0.00000583

AC XY:

AN XY:

686460

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31466

American (AMR)

AF:

0.00

AC:

AN:

35528

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25102

East Asian (EAS)

AF:

0.00

AC:

AN:

35706

South Asian (SAS)

AF:

0.00

AC:

AN:

79100

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43740

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4562

European-Non Finnish (NFE)

AF:

0.0000167

AC:

AN:

1078530

Other (OTH)

AF:

0.00

AC:

AN:

57782

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41476

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.46

CADD

Benign

9.0

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.11

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.40

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.081

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

0.12

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.30

REVEL

Benign

0.075

Sift

Pathogenic

0.0

Sift4G

Benign

0.26

Polyphen

0.041

Vest4

0.082

MutPred

0.084

Loss of helix (P = 0.0093)

MVP

0.28

MPC

0.080

ClinPred

0.26

GERP RS

1.7

PromoterAI

-0.015

Neutral

(source)

Varity_R

0.33

gMVP

0.069

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over